Method for preparing dehydroabietyl 1, 2, 4-triazolethione bactericide

Abstract

The invention belongs to the technical field of fine chemical engineering and bactericides, and relates to a dehydroabietyl 1, 2, 4-triazolethione bactericide and a preparation method thereof.The preparation method comprises the steps that firstly, dehydroabietic aldehyde and anhydrous hydrazine are subjected to a condensation reaction for 2-10 h in an alcohol solvent at the temperature of 40-100 DEG C according to the molar ratio of 1: 2-1: 4, and dehydroabietic hydrazine is generated; then, carrying out cyclization reaction on the dehydroabietic hydrazine and an isothiocyanate compound in a polar aprotic solvent according to a molar ratio of (1: 1)-(1: 2), so as to obtain dehydroabietyl 1, 2, 4-triazolidinethione; and finally, carrying out oxidation reaction for 4-10 hours at 40-80 DEG C by taking oxygen or air as an oxidizing agent, and filtering, washing and drying to obtain a target product. The dehydrorosin group and the triazolethione group in the product structure have good synergistic bactericidal activity, the preparation steps are few, the yield is high, and the purity is high; in addition, the natural dehydrorosin raw material has good biocompatibility, and has potential application value in the fields of pesticides, medicines and the like.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of fine chemical technology, namely a dehydroabietyl 1,2,4-triazole thione fungicide with high efficiency and a synthesis method thereof. BACKGROUND

[0002] Food security is the core issue of global sustainable development, and crop diseases, as a key factor restricting food production, have posed a serious challenge to agricultural economy and food supply. According to the statistics of the Food and Agriculture Organization of the United Nations, the annual crop diseases caused by fungal, bacterial and other pathogenic bacteria lead to more than 15% reduction in food production, with economic losses of up to 220 billion US dollars. Among them, wheat scab, cucumber fusarium wilt and other diseases have become a disaster area threatening the production of staple foods and economic crops due to their fast spread and strong pathogenicity. With the acceleration of climate change and pathogen variation, the control effect of traditional fungicides continues to decline, and the development of new fungicides with high efficiency and environmental safety has become an urgent need in the field of agricultural science and technology.

[0003] Although the current mainstream triazole fungicides are widely used in agricultural production, they have some technical limitations that are difficult to overcome. CN106243087B discloses a synthesis method of triazole pyrrolidone fungicide, which uses triazole amide ketone compounds as raw materials, and is subjected to intramolecular dehydration condensation and ring closure reaction in ethanol-water mixed solvent under the catalysis of potassium carbonate to obtain the product. This method has short steps and high yield, but has some limitations such as the solvent system producing salt-containing wastewater, low inhibition rate (≤64%) to wheat scab and fusarium wilt, and large amount of potassium carbonate leading to complex product purification. CN105017232B discloses a synthesis method of triazole fungicide, which condenses 4-amino-1,2,4-triazole and halogenated compound in an organic solvent to obtain an organic salt, and then performs deamination reaction with dilute hydrochloric acid and sodium nitrite aqueous solution to obtain the product. This method avoids the generation of 1,3,4-triazole by-product, and the yield can reach 95%, but the deamination step requires low temperature conditions, which increases the industrialization cost, and the reaction easily produces toxic nitrosyl chloride gas, which needs complex tail gas treatment and is only suitable for halogenated epoxy substrates, and cannot be compatible with complex skeletons derived from natural products. In addition, the initial raw materials of the above-mentioned fungicides are chemical synthetic substances, and the biocompatibility and degradation performance of the obtained products are poor, which further leads to long residual period in the environment, high ecological risk, and may have negative effects on soil microbial communities, limiting their sustainable application.

[0004] Dehydroabietyl aldehyde is derived from natural rosin, and its tricyclic diterpene skeleton has good biocompatibility and biodegradability. The hydrophobic group in the molecule can bind to the lipid bilayer of the cell membrane of pathogenic bacteria through van der Waals force, thereby enhancing the penetration of the substance. At the same time, its rigid structure can improve the molecular stability and reduce the environmental toxicity. The 1,2,4-triazole thione compound can inhibit the activity of the cytochrome P450 enzyme system of pathogenic bacteria through coordination, block the metabolic pathway, and exhibit broad-spectrum antibacterial activity. Therefore, the two types of structures are fused in the application, and a significant synergistic effect is generated: the dehydroabietyl group provides a cell membrane penetration channel for the triazole thione group through hydrophobic interaction, thereby increasing the intracellular drug concentration; the triazole thione group precisely targets the metabolic target of pathogenic bacteria, and the synergistic effect of the two improves the antibacterial efficiency by 3-5 times, reduces the minimum inhibitory concentration (MIC) by more than 50%, and the fused molecule retains the low toxicity and environmental compatibility of natural products. SUMMARY

[0005] The application aims to provide a dehydroabietyl 1,2,4-triazole thione bactericide and a synthesis method thereof. Based on the good synergistic bactericidal activity between the dehydroabietyl group and the triazole thione group in the product structure and the good biocompatibility and low environmental toxicity of the compound itself, the defects of the existing 1,2,4-triazole thione bactericide, such as the use of chemically synthesized initial raw materials, poor biocompatibility, and difficulty in degradation, are solved.

[0006] The application relates to a method for preparing a dehydroabietyl 1,2,4-triazole thione bactericide, characterized in that the bactericide has the structural expression of:

[0007]

[0008] wherein R is one of methyl, ethyl, n-propyl, isopropyl, n-butyl, benzyl, diphenylmethyl, n-octyl, n-dodecyl or n-octadecyl; in the preparation, dehydroabietyl aldehyde is condensed with anhydrous hydrazine in an alcohol solvent to generate dehydroabietyl hydrazine, then the dehydroabietyl hydrazine is subjected to a ring-closing reaction with an alkyl-substituted isothiocyanate compound in a polar aprotic solvent to generate 1-dehydroabietyl-4-alkyl-1,2,4-triazole alkylthione, and then an oxidation reaction is performed to obtain the 1-dehydroabietyl-4-alkyl-1,2,4-triazole thione bactericide.

[0009] The molar ratio of the dehydroabietinal to the anhydrous hydrazine is 1:2-1:4, the alcohol solvent is added in an amount of 5 times of the dehydroabietinal, the condensation reaction temperature is 40-100 DEG C, and the reaction time is 2-10h; after the reaction is completed, the temperature is cooled to 5 DEG C, the filter cake is filtered, washed with the alcohol solvent at 5 DEG C for three times, and dried in vacuum to obtain the dehydroabietyl hydrazine; the alcohol solvent is one of methanol, ethanol, n-propanol, isopropanol and n-butanol.

[0010] The molar ratio of the dehydroabietyl hydrazine to the alkyl substituted isothiocyanate compound is 1:1-1:2, the polar aprotic solvent is 4 times of the mass number of the dehydroabietyl hydrazine, the cyclization reaction temperature is 60-100 DEG C, and the reaction time is 4-10h; after the reaction, the polar aprotic solvent is recovered by distillation under reduced pressure, the obtained residue is added with ethyl acetate in an equal mass, and the temperature is increased to reflux, then slowly cooled to 5 DEG C to wash out the crystal, the filter cake is filtered, washed with the ethyl acetate at 5 DEG C for three times, and dried in vacuum to obtain the 1-dehydroabietyl-4-alkyl-1,2,4-triazole dithiolane thione; the polar aprotic solvent used in the cyclization reaction is one of acetonitrile, N,N-dimethylformamide and dimethyl sulfoxide.

[0011] The oxidation reaction uses oxygen or air as the oxidant, and the alcohol solvent in claim 2 as the solvent, the alcohol solvent is added in an amount of 4 times of the mass number of the 1-dehydroabietyl-4-alkyl-1,2,4-triazole dithiolane thione, the initial pressure of the air or oxygen is 3-6 MPa, the reaction temperature is 40-80 DEG C, and the reaction time is 4-10h; after the reaction is completed, the temperature is cooled to 5 DEG C, the pressure is released, the kettle is opened, the reaction mixture is filtered, the filter cake is washed with the alcohol solution at 5 DEG C for three times, and dried to obtain the product 1-dehydroabietyl-4-alkyl-1,2,4-triazole thione fungicide.

[0012] The alkyl in the alkyl substituted isothiocyanate compound is one of methyl, ethyl, n-propyl, isopropyl, n-butyl, benzyl, diphenylmethyl, n-octyl, n-dodecyl or n-octadecyl.

[0013] In addition, the above-mentioned method includes the main synthesis path as follows:

[0014] 1. The dehydroabietinal reacts with the hydrazine to generate the dehydroabietyl hydrazine, and the reaction formula is as follows:

[0015]

[0016] 2. The dehydroabietyl hydrazine reacts with the alkyl isothiocyanate to generate the 1-dehydroabietyl-4-alkyl-1,2,4-triazole dithiolane thione, and the reaction formula is as follows:

[0017]

[0018] 3.1-dehydroabietyl-4-alkyl-1,2,4-triazolethione is prepared by oxidation reaction of 1-dehydroabietyl-4-alkyl-1,2,4-triazolethiolane, and the reaction formula is as follows:

[0019]

[0020] The comprehensive reaction equation is as follows:

[0021]

[0022] The specific technical solutions are described by taking the preparation of 1-dehydroabietyl-4-ethyl-1,2,4-triazolethione as an example:

[0023] 0.1 mol of dehydroabietaldehyde, 0.3 mol of anhydrous hydrazine, and 5 times the mass of dehydroabietaldehyde of ethanol are added to the reaction kettle, and the temperature is raised to 70°C for stirring reaction for 5 h. After cooling to 5°C, the filter cake is filtered, washed with 5°C ethanol for three times, and vacuum dried to obtain white solid dehydroabietaldehyde hydrazine with a yield of 94.5% and a purity of 98.0%. 0.05 mol of the above dehydroabietaldehyde hydrazine, 0.075 mol of ethyl isothiocyanate, and 4 times the mass of dehydroabietaldehyde hydrazine of polar aprotic solvent acetonitrile are added to the reaction kettle, and the temperature is raised to 80°C for reaction for 6 h. After recovering acetonitrile by reduced pressure distillation, the obtained distillation residue is added with ethyl acetate with the same mass, and the temperature is raised to reflux. Then, the temperature is slowly lowered to 5°C to wash out the crystals. After filtration, the filter cake is washed with 5°C ethyl acetate for three times, and vacuum dried to obtain 1-dehydroabietyl-4-ethyl-1,2,4-triazolethione with a yield of 91.6% and a purity of 95.8%. 0.03 mol of 1-dehydroabietyl-4-ethyl-1,2,4-triazolethione and 4 times the mass of ethanol are added to the reactor, and oxygen is filled with an initial pressure of 4 MPa. The temperature is raised to 60°C for reaction for 6 h. After reaction, the temperature is cooled to 5°C, the pressure is released, the kettle is opened, the reaction mixture is filtered, the filter cake is washed with 5°C ethanol solution for three times, and dried to obtain the product 1-dehydroabietyl-4-ethyl-1,2,4-triazolethione fungicide with a yield of 88.5% and a purity of 96.2%.

[0024] The prepared fungicide is tested for fungicidal performance as follows: the fungicide 1-dehydroabietyl-4-ethyl-1,2,4-triazolethione prepared in the above examples is tested for antibacterial activity by using the mycelial growth rate method. The wheat scab fungus is used as the test fungus, and different concentrations of the fungicide solution are added to the culture dish containing the culture medium, the culture medium is PDA medium (potato 200 g / L, glucose 20 g / L, agar 15 g / L), and the culture is carried out at 25°C for 72 h, the fungus cake diameter is 5 mm, the concentration gradient of the fungicide is set to 5, 10, 15, 20 μg / mL, each group is repeated 3 times, and the minimum inhibitory concentration (MIC) is calculated. The results show that the MIC of 1-dehydroabietyl-4-ethyl-1,2,4-triazolethione for the wheat scab fungus is 14.5 μg / mL, which is significantly lower than that of the traditional triazole fungicide (such as the dicyclometoxazole of Comparative Example 2, MIC = 28.3 μg / mL), indicating that the fungicide has outstanding advantages in fungicidal activity.

[0025] Compared with the traditional method, the characteristics of the present application are:

[0026] 1. The natural dehydroabietyl is used as the raw material, the unique tricyclic diterpene skeleton has good biocompatibility and renewability, and the limitation of traditional fungicides relying on chemical synthesis of raw materials is broken. The fusion of the tricyclic diterpene skeleton and the 1,2,4-triazolethione structure forms a new molecular skeleton, which not only retains the low toxicity advantage of natural products, but also provides a structural basis for improving fungicidal activity, and realizes the high-value utilization of natural resources.

[0027] 2. The dehydroabietyl group and the 1,2,4-triazolethione form a synergistic structure, the former penetrates the pathogenic fungus cell membrane through hydrophobic interaction, and the latter precisely targets the cytochrome P450 enzyme system, the functions of the two are complementary, the antibacterial efficiency is significantly improved, the minimum inhibitory concentration is reduced by more than 50%, and the bottleneck of single structure fungicide mechanism is broken.

[0028] 3. The oxidation step uses oxygen or air as the oxidant, does not need a metal catalyst, and the byproduct is only water, avoiding pollution in the traditional process, realizing the dual breakthroughs of clean production and low-cost industrialization. DETAILED DESCRIPTION

[0029] The method of the present application is further described below in conjunction with examples, which are not limitations of the present application.

[0030] Example 1

[0031] Into a reactor, 0.1 mol of dehydroabietyl aldehyde, 0.3 mol of anhydrous hydrazine, and 5 times the mass of dehydroabietyl aldehyde of ethanol were added, and the reaction was stirred at 70°C for 5 h. After cooling to 5°C, the mixture was filtered, the filter cake was washed with 5°C ethanol three times, and vacuum drying was performed to obtain white solid dehydroabietyl hydrazine with a yield of 94.5% and a purity of 98.0%. Into a reactor, 0.05 mol of the above dehydroabietyl hydrazine, 0.075 mol of ethyl isothiocyanate, and 4 times the mass of dehydroabietyl hydrazine of acetonitrile were added, and the reaction was performed at 80°C for 6 h. After recovering acetonitrile by distillation under reduced pressure, the obtained distillation residue was added with ethyl acetate in an equal mass, and the mixture was heated to reflux. Then, the mixture was slowly cooled to 5°C to wash out the crystals. After filtration, the filter cake was washed with 5°C ethyl acetate three times, and vacuum drying was performed to obtain 1-dehydroabietyl-4-ethyl-1,2,4-triazolane thione with a yield of 91.6% and a purity of 95.8%. Into a reactor, 0.03 mol of 1-dehydroabietyl-4-ethyl-1,2,4-triazolane thione and 4 times the mass of 1-dehydroabietyl-4-ethyl-1,2,4-triazolane thione of ethanol were added, and oxygen was filled into the reactor at an initial pressure of 4 MPa. The mixture was heated to 60°C and reacted for 6 h. After the reaction was completed, the mixture was cooled to 5°C, the pressure was released, the reactor was opened, the reaction mixture was filtered, the filter cake was washed with 5°C ethanol solution three times, and drying was performed to obtain the product 1-dehydroabietyl-4-ethyl-1,2,4-triazolone fungicide with a yield of 88.5% and a purity of 96.2%. The product was tested for fungicidal performance, and the MIC of the product against Fusarium graminearum was 14.5 μg / mL.

[0032]

[0033] Comparative Example 1

[0034] Into a reactor, 0.1 mol of N-(2-(4-chlorophenyl)-2-oxoethyl)-N-(4-fluorophenyl)-2-(1H-1,2,4-triazole)acetamide and 0.15 mol of potassium carbonate were added into 100 mL of an ethanol-water mixed solvent (Vethanol:Vwater = 1:1), and the mixture was stirred at 40°C for 1 h. A large amount of solid appeared in the system, and TLC monitoring showed that the reaction was completed. After filtration and drying, 4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-(1H-1,2,4-triazole)-1H-pyrrol-2(5H)-one white solid was obtained with a yield of 78.5% and a purity of 96.3%. The product was tested for fungicidal performance, and the MIC of the product against Fusarium graminearum was 22.5 μg / mL.

[0035] Comparative Example 2

[0036] 0.1 mol of bromoepoxy and 0.12 mol of 4-amino-1,2,4-triazole were added into 100 mL of diethylene glycol dimethyl ether, and the mixture was stirred at 80°C for 8 h. After cooling, the organic salt wet product was filtered and washed to obtain a dry product with a yield of 89.2%. 0.05 mol of the organic salt was dissolved in 120 g of 10% dilute hydrochloric acid, and the temperature was lowered to 5°C. 0.15 mol of 25% sodium nitrite aqueous solution was added dropwise, and the mixture was reacted at room temperature for 2 h. After the pH was adjusted to neutral, the mixture was separated, decolorized, and crystallized to obtain a white solid of difenoconazole with a yield of 80.8% and a purity of 96.5%. The product was tested for fungicidal performance, and the MIC of the product against Fusarium graminearum was 28.3 μg / mL.

[0037] Example 2

[0038] 0.1 mol of dehydroabietyl aldehyde, 0.2 mol of anhydrous hydrazine, and 5 times the amount of dehydroabietyl aldehyde in methanol were added into a reaction kettle, and the mixture was stirred at 40°C for 10 h. After cooling to 5°C, the mixture was filtered, and the filter cake was washed with 5°C methanol three times and dried under vacuum to obtain white solid dehydroabietyl hydrazine with a yield of 92.4% and a purity of 98.2%. 0.05 mol of the dehydroabietyl hydrazine, 0.05 mol of methyl isothiocyanate, and 4 times the amount of dehydroabietyl hydrazine in acetonitrile were added into a reaction kettle, and the mixture was reacted at 60°C for 10 h. After recovering acetonitrile by distillation under reduced pressure, the obtained distillation residue was added with ethyl acetate in an equal amount, and the mixture was heated to reflux and then slowly cooled to 5°C to wash out the crystals. The mixture was filtered, the filter cake was washed with 5°C ethyl acetate three times, and then dried under vacuum to obtain 1-dehydroabietyl-4-methyl-1,2,4-triazolidine thione with a yield of 89.0% and a purity of 96.6%. 0.03 mol of 1-dehydroabietyl-4-methyl-1,2,4-triazolidine thione and 4 times the amount of methanol were added into a reactor, and air was filled into the reactor at an initial pressure of 6 MPa. The mixture was heated to 40°C and reacted for 10 h. After cooling to 5°C, the pressure was released, the reactor was opened, the reaction mixture was filtered, the filter cake was washed with 5°C methanol three times, and then dried to obtain the product 1-dehydroabietyl-4-methyl-1,2,4-triazolidine thione fungicide with a yield of 87.1% and a purity of 95.2%. The product was tested for fungicidal performance, and the MIC of the product against Fusarium graminearum was 14.5 μg / mL.

[0039]

[0040] Example 3

[0041] The 0.1 mol dehydroabietinal, 0.4 mol anhydrous hydrazine, dehydroabietinal mass number 5 times of n-propanol into the reactor, heated to 100 ℃ under stirring reaction 2 h, cooling to 5 ℃ after filtration, 5 ℃ n-propanol wash filter cake three times, vacuum drying, obtained white solid dehydroabietinal hydrazine, its yield 93.6 %, purity 97.9 %; take 0.05 mol of the above dehydroabietinal hydrazine, 0.1 mol of n-propyl isothiocyanate, dehydroabietinal hydrazine mass number 4 times of polar aprotic solvent N, N-dimethylformamide into the reactor, heated to 100 ℃ reaction 4 h, after recovering N, N-dimethylformamide under reduced pressure distillation, the obtained distillation residue solid added with its equal mass of ethyl acetate, heated to reflux, slowly cooled to 5 ℃ wash out the crystal, filtration, filter cake with 5 ℃ ethyl acetate wash three times, and vacuum drying, 1-dehydroabietinyl-4-n-propyl-1, 2, 4-triazole alkylthio ketone, its yield 90.2 %, purity 96.0 %; 0.03 mol 1-dehydroabietinyl-4-n-propyl-1, 2, 4-triazole alkylthio ketone and its mass number 4 times of n-propanol in the reactor, filled with air initial pressure of 6 MPa, heated to 80 ℃ for 4 h; after reaction, cooling to 5 ℃, unloading pressure, open kettle, filter the reaction mixture, with 5 ℃ n-propanol solution wash filter cake three times, drying, 1-dehydroabietinyl-4-n-propyl-1, 2, 4-triazole alkylthio ketone fungicide, its yield 87.0 %, purity 95.8 %. The product was tested for fungicidal performance, the product on the MIC of wheat scab fungus is 15.3 μg / mL.

[0042]

[0043] Example 4

[0044] The reaction kettle was charged with 0.1 mol dehydroabietinal, 0.3 mol anhydrous hydrazine, and 5 times the mass of dehydroabietinal of n-butanol, and the temperature was raised to 80°C for stirring reaction for 4 h. After cooling to 5°C, the filter cake was filtered, washed with 5°C n-butanol three times, and vacuum dried to obtain white solid dehydroabietinal hydrazine with a yield of 94.5% and a purity of 97.0%. The reaction kettle was charged with 0.05 mol of the above dehydroabietinal hydrazine, 0.15 mol of n-butyl isothiocyanate, and 4 times the mass of dehydroabietinal hydrazine of polar aprotic solvent dimethyl sulfoxide, and the temperature was raised to 80°C for reaction for 6 h. After recovering dimethyl sulfoxide by reduced pressure distillation, the obtained distillation residue was added with ethyl acetate in an equal mass, and the temperature was raised to reflux, then slowly cooled to 5°C to wash out the crystals. After filtration, the filter cake was washed with 5°C ethyl acetate three times, and vacuum dried to obtain 1-dehydroabietyl-4-n-butyl-1,2,4-triazole alkane thio ketone with a yield of 91.1% and a purity of 96.4%. The reactor was charged with 0.03 mol of 1-dehydroabietyl-4-n-butyl-1,2,4-triazole alkane thio ketone and 4 times the mass of n-butanol, and air was filled to an initial pressure of 4 MPa. The temperature was raised to 60°C for reaction for 6 h. After reaction, the temperature was cooled to 5°C, the pressure was released, the kettle was opened, the reaction mixture was filtered, the filter cake was washed with 5°C n-butanol solution three times, and dried to obtain the product 1-dehydroabietyl-4-n-butyl-1,2,4-triazole thio ketone fungicide with a yield of 87.6% and a purity of 96.5%. The product was tested for fungicidal performance, and the MIC of the product on wheat scab fungus was 15.8 μg / mL.

[0045]

[0046] Example 5

[0047] The 0.1 mol dehydroabietinal, 0.25 mol anhydrous hydrazine, dehydroabietinal mass number 5 times of isopropanol into the reactor, heated to 80 ℃ under stirring reaction 5 h, cooling to 5 ℃ after filtration, 5 ℃ isopropanol washing filter cake three times, vacuum drying, to obtain white solid dehydroabietinal hydrazine, its yield 95.0%, purity 97.7%; take 0.05 mol of the above dehydroabietinal hydrazine, 0.1 mol isopropyl isothiocyanate, dehydroabietinal hydrazine mass number 4 times of polar aprotic solvent dimethyl sulfoxide into the reactor, heated to 70 ℃ reaction 6 h, after recovery of dimethyl sulfoxide under reduced pressure distillation, the obtained distillation residue solid added with its equal mass of ethyl acetate, heated to reflux, slowly cooled to 5 ℃ washing crystal, filtration, filter cake with 5 ℃ ethyl acetate washing three times, and vacuum drying, 1-dehydroabietinyl-4-isopropyl-1,2,4-triazole dithiolthione, its yield 92.3%, purity 96.6%; 0.03 mol 1-dehydroabietinyl-4-isopropyl-1,2,4-triazole dithiolthione and its mass number 4 times of isopropanol in the reactor, filled with air initial pressure of 4.5 MPa, heated to 50 ℃ for 5 h; after reaction, cooling to 5 ℃, pressure relief, open pot, filter the reaction mixture, with 5 ℃ isopropanol solution washing filter cake three times, drying, 1-dehydroabietinyl-4-isopropyl-1,2,4-triazole dithiolthione fungicide, its yield 88.2%, purity 97.0%. The product was tested for fungicidal performance, the product on the MIC of wheat scab fungus is 15.4 μg / mL.

[0048]

[0049] Example 6

[0050] The reaction kettle was charged with 0.1 mol of dehydroabietyl aldehyde, 0.4 mol of anhydrous hydrazine, 5 times the mass of dehydroabietyl aldehyde of ethanol, and the reaction was stirred at 70°C for 6 h. After cooling to 5°C, the filter cake was filtered, washed with 5°C ethanol three times, and vacuum dried to obtain white solid dehydroabietyl hydrazine with a yield of 95.6% and a purity of 97.2%. The reaction kettle was charged with 0.05 mol of the above dehydroabietyl hydrazine, 0.1 mol of benzyl isothiocyanate, and 4 times the mass of dehydroabietyl hydrazine of dimethyl sulfoxide, and the reaction was stirred at 80°C for 6 h. After recovering dimethyl sulfoxide by distillation under reduced pressure, the obtained distillation residue was added with an equal mass of ethyl acetate, and the mixture was heated to reflux, then slowly cooled to 5°C to wash out the crystals. The crystals were filtered, the filter cake was washed with 5°C ethyl acetate three times, and vacuum dried to obtain 1-dehydroabietyl-4-benzyl-1,2,4-triazolidine thione with a yield of 92.6% and a purity of 97.0%. The reactor was charged with 0.03 mol of 1-dehydroabietyl-4-benzyl-1,2,4-triazolidine thione and 4 times the mass of ethanol, and air was filled to an initial pressure of 3 MPa. The mixture was heated to 60°C and reacted for 5 h. After the reaction, the mixture was cooled to 5°C, depressurized, opened, filtered, washed with 5°C ethanol three times, and dried to obtain the product 1-dehydroabietyl-4-benzyl-1,2,4-triazolidine thione fungicide with a yield of 87.2% and a purity of 97.1%. The product was tested for fungicidal performance, and the MIC of the product against wheat scab fungus was 15.7 μg / mL.

[0051]

[0052] Example 7

[0053] The reaction kettle was charged with 0.1 mol dehydroabietinal, 0.3 mol anhydrous hydrazine, 5 times the mass of dehydroabietinal of methanol, and stirred at 80°C for 3 h. After cooling to 5°C, the filter cake was filtered, washed with 5°C methanol three times, and vacuum dried to obtain white solid dehydroabietinal hydrazine with a yield of 95.7% and a purity of 97.5%. The reaction kettle was charged with 0.05 mol of the above dehydroabietinal hydrazine, 0.15 mol of benzhydryl isothiocyanate, and 4 times the mass of dehydroabietinal hydrazine of dimethyl sulfoxide, and stirred at 70°C for 6 h. After recovering dimethyl sulfoxide by reduced pressure distillation, the obtained distillation residue was added with an equal mass of ethyl acetate, heated to reflux, slowly cooled to 5°C to wash out the crystals, filtered, washed the filter cake with 5°C ethyl acetate three times, and vacuum dried to obtain 1-dehydroabietyl-4-benzhydryl-1,2,4-triazolidine thione with a yield of 92.5% and a purity of 97.3%. The reactor was charged with 0.03 mol of 1-dehydroabietyl-4-benzhydryl-1,2,4-triazolidine thione and 4 times the mass of methanol, and filled with air with an initial pressure of 3 MPa, heated to 70°C for 5 h. After cooling to 5°C, the pressure was released, the reactor was opened, the reaction mixture was filtered, the filter cake was washed with 5°C methanol solution three times, and dried to obtain the product 1-dehydroabietyl-4-benzhydryl-1,2,4-triazole thione fungicide with a yield of 87.7% and a purity of 97.4%. The product was tested for fungicidal performance, and the MIC of the product against wheat scab fungus was 15.6 μg / mL.

[0054]

[0055] Example 8

[0056] The reaction kettle was charged with 0.1 mol dehydroabietinal, 0.25 mol anhydrous hydrazine, 5 times the mass of dehydroabietinal of n-butanol, and the reaction was stirred at 80°C for 5 h. After cooling to 5°C, the filter cake was filtered, washed with n-butanol at 5°C for three times, and vacuum dried to obtain white solid dehydroabietinal hydrazine with a yield of 96.1% and a purity of 97.7%. 0.05 mol of the above dehydroabietinal hydrazine, 0.1 mol of n-octyl isothiocyanate, and 4 times the mass of dehydroabietinal hydrazine of polar aprotic solvent dimethyl sulfoxide were added to the reaction kettle, and the reaction was carried out at 70°C for 7 h. After recovering dimethyl sulfoxide by reduced pressure distillation, the obtained distillation residue was added with ethyl acetate in an equal mass, and after heating to reflux, the temperature was slowly lowered to 5°C to wash out the crystals. The crystals were filtered, the filter cake was washed with ethyl acetate at 5°C for three times, and vacuum dried to obtain 1-dehydroabietyl-4-n-octyl-1,2,4-triazole alkane thione with a yield of 93.2% and a purity of 97.8%. 0.03 mol of 1-dehydroabietyl-4-n-octyl-1,2,4-triazole alkane thione and 4 times the mass of n-butanol were added to the reactor, and air was filled to an initial pressure of 5 MPa. The temperature was raised to 70°C, and the reaction was carried out for 7 h. After the reaction, the temperature was lowered to 5°C, the pressure was released, the reactor was opened, the reaction mixture was filtered, the filter cake was washed with n-butanol at 5°C for three times, and dried to obtain the product 1-dehydroabietyl-4-n-octyl-1,2,4-triazole thione fungicide with a yield of 87.9% and a purity of 97.7%. The product was tested for its fungicidal performance, and the MIC of the product against wheat scab fungus was 15.6 μg / mL.

[0057]

[0058] Example 9

[0059] The reaction kettle was charged with 0.1 mol of dehydroabietyl aldehyde, 0.3 mol of anhydrous hydrazine, and 5 times the mass of dehydroabietyl aldehyde of methanol, and stirred at 80°C for 6 h. After cooling to 5°C, the mixture was filtered, the filter cake was washed with 5°C methanol three times, and vacuum dried to obtain white solid dehydroabietyl hydrazine with a yield of 96.7% and a purity of 96.0%. The reaction kettle was charged with 0.05 mol of the above dehydroabietyl hydrazine, 0.15 mol of n-dodecyl isothiocyanate, and 4 times the mass of dehydroabietyl hydrazine of dimethyl sulfoxide, and stirred at 80°C for 6 h. After recovering dimethyl sulfoxide by distillation under reduced pressure, the obtained distillation residue was added with ethyl acetate in an equal mass, and heated to reflux. The mixture was slowly cooled to 5°C to wash out the crystals. The mixture was filtered, the filter cake was washed with 5°C ethyl acetate three times, and vacuum dried to obtain 1-dehydroabietyl-4-n-dodecyl-1,2,4-triazolidine thione with a yield of 93.7% and a purity of 97.9%. The reaction kettle was charged with 0.03 mol of 1-dehydroabietyl-4-n-dodecyl-1,2,4-triazolidine thione and 4 times the mass of methanol, and filled with air at an initial pressure of 5 MPa. The mixture was heated to 70°C and maintained for 7 h. After cooling to 5°C, the mixture was discharged, filtered, and the filter cake was washed with 5°C methanol three times and dried to obtain the product 1-dehydroabietyl-4-n-dodecyl-1,2,4-triazolidine thione fungicide with a yield of 87.4% and a purity of 98.1%. The product was tested for fungicidal performance, and the MIC of the product against wheat scab fungus was 15.9 μg / mL.

[0060]

[0061] Example 10

[0062] The reaction kettle was charged with 0.1 mol dehydroabietinal, 0.2 mol anhydrous hydrazine, 5 times the mass of dehydroabietinal of methanol, and stirred at 80°C for 5 h. After cooling to 5°C, the mixture was filtered, the filter cake was washed with methanol at 5°C for three times, and vacuum dried to obtain white solid dehydroabietinal hydrazine with a yield of 96.9% and a purity of 96.7%. The reaction kettle was charged with 0.05 mol of the above dehydroabietinal hydrazine, 0.15 mol of n-octadecyl isothiocyanate, and 4 times the mass of dehydroabietinal hydrazine of dimethyl sulfoxide, and stirred at 80°C for 7 h. After recovering dimethyl sulfoxide by distillation under reduced pressure, the obtained distillation residue was added with ethyl acetate in an equal mass, heated to reflux, slowly cooled to 5°C to wash out the crystals, filtered, the filter cake was washed with ethyl acetate at 5°C for three times, and vacuum dried to obtain 1-dehydroabietyl-4-n-octadecyl-1,2,4-triazolidine thione with a yield of 94.0% and a purity of 98.1%. The reactor was charged with 0.03 mol of 1-dehydroabietyl-4-n-octadecyl-1,2,4-triazolidine thione and 4 times the mass of 1-dehydroabietyl-4-n-octadecyl-1,2,4-triazolidine thione of methanol, and filled with air with an initial pressure of 4 MPa, and stirred at 80°C for 7 h. After cooling to 5°C, the pressure was released, the reactor was opened, the reaction mixture was filtered, the filter cake was washed with methanol at 5°C for three times, and dried to obtain the product 1-dehydroabietyl-4-n-octadecyl-1,2,4-triazole thione fungicide with a yield of 87.6% and a purity of 98.4%. The product was tested for fungicidal performance, and the MIC of the product against Fusarium graminearum was 15.6 μg / mL.

[0063]

[0064] The above 10 fungicides were tested for their killing performance against Fusarium graminearum, Botrytis cinerea, and Physalospora piricola. The test results of different dehydroabietyl 1,2,4-triazolidine thione fungicides obtained by reacting different R group isothiocyanates are shown in Table 1.

[0065] The MIC of the dehydroabietyl 1,2,4-triazolidine thione fungicide against the three tested pathogens was 14.5-15.9 μg / mL, 19.4-25.3 μg / mL, and 27.5-30.5 μg / mL, which was significantly lower than that of the traditional triazole fungicide (such as the dicyclomet fungicide in Comparative Example 2, MIC = 28.3 μg / mL, 33.5 μg / mL, and 50.1 μg / mL), indicating that the fungicide had outstanding advantages in fungicidal activity.

[0066] Table 1 MIC data of three pathogens under the fungicidal action of different dehydroabietyl 1,2,4-triazolidine thione fungicides

[0067]

[0068]

[0069] The above examples are only used to illustrate the technical solutions of the present application, but not to limit the present application; although the present application has been described in detail with reference to the foregoing examples, modifications can still be made by those of ordinary skill in the art to the technical solutions described in the foregoing examples, or equivalent replacements can be made to some of the technical features; and these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions claimed by the present application.

Claims

1. A process for the preparation of dehydroabietyl 1,2,4-triazole thione fungicides, characterized in that The bactericide structure expression is: Wherein, R is one of methyl, ethyl, n-propyl, isopropyl, n-butyl, benzyl, diphenylmethyl, n-octyl, n-dodecyl or n-octadecyl; in preparation, dehydroabietinal is condensed with anhydrous hydrazine in alcohol solvent to generate dehydroabietinal hydrazine, then the dehydroabietinal hydrazine is cyclized with alkyl-substituted isothiocyanate compound in polar aprotic solvent to generate 1-dehydroabietyl-4-alkyl-1,2,4-triazole alkylthione, and then oxidation reaction is carried out to generate 1-dehydroabietyl-4-alkyl-1,2,4-triazole alkylthione bactericide.

2. The molar ratio of the dehydroabietinal and anhydrous hydrazine in claim 1 is 1:2-1:4, the alcohol solvent is added in an amount of 5 times of the dehydroabietinal, the condensation reaction temperature is 40-100℃, and the reaction time is 2-10h; after the reaction is completed, cooling is carried out to 5℃, filtration is carried out, the filter cake is washed with 5℃ alcohol solvent for three times, and vacuum drying is carried out to obtain the dehydroabietinal hydrazine; the alcohol solvent is one of methanol, ethanol, n-propanol, isopropanol and n-butanol.

3. The molar ratio of the dehydroabietinal hydrazine and alkyl-substituted isothiocyanate compound in claim 1 is 1:1-1:2, the polar aprotic solvent is 4 times of the mass number of the dehydroabietinal hydrazine, the cyclization reaction temperature is 60-100℃, and the reaction time is 4-10h; after the reaction, the polar aprotic solvent is recovered by reduced pressure distillation, the obtained residue is added with ethyl acetate in an equal mass, and after being heated to reflux, the temperature is slowly reduced to 5℃ to wash out the crystal, filtration is carried out, the filter cake is washed with 5℃ ethyl acetate for three times, and vacuum drying is carried out to obtain 1-dehydroabietyl-4-alkyl-1,2,4-triazole alkylthione; the polar aprotic solvent used in the cyclization reaction is one of acetonitrile, N,N-dimethylformamide and dimethyl sulfoxide.

4. The oxidation reaction in claim 1 uses oxygen or air as the oxidant, and the alcohol solvent in claim 2 is used as the solvent, the alcohol solvent is added in an amount of 4 times of the mass number of 1-dehydroabietyl-4-alkyl-1,2,4-triazole alkylthione, the initial pressure of the filled air or oxygen is 3-6MPa, the reaction temperature is 40-80℃, and the reaction time is 4-10h; after the reaction is completed, cooling is carried out to 5℃, filtration is carried out, the filter cake is washed with 5℃ alcohol solution for three times, and drying is carried out to obtain the product 1-dehydroabietyl-4-alkyl-1,2,4-triazole alkylthione bactericide.

5. The alkyl in the alkyl-substituted isothiocyanate compound in claim 1 is one of methyl, ethyl, n-propyl, isopropyl, n-butyl, benzyl, diphenylmethyl, n-octyl, n-dodecyl or n-octadecyl.

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